The In Vitro Efficacy of Antimicrobial Agents Against the Pathogenic Free-Living Amoeba Balamuthia mandrillaris

2013 ◽  
Vol 60 (5) ◽  
pp. 539-543 ◽  
Author(s):  
Arine F. Ahmad ◽  
Wayne Heaselgrave ◽  
Peter W. Andrew ◽  
Simon Kilvington
Keyword(s):  
Antimicrobial Agents ◽  
Free Living ◽  
Balamuthia Mandrillaris ◽  
Free Living Amoeba

Balamuthia mandrillaris: A Rare Free-Living Amoeba

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Jessica Chan ◽  
Mirella Mircescu ◽  
Pratik Shah ◽  
Andrew Liguori ◽  
Aaron Shmookler
Keyword(s):  
Free Living ◽  
Balamuthia Mandrillaris ◽  
Free Living Amoeba

scholarly journals In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria and Pathogen Boxes To Discover Novel Compounds with Activity against Balamuthia mandrillaris

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Christopher A. Rice ◽  
Luis Fernando Lares-Jiménez ◽  
Fernando Lares-Villa ◽  
Dennis E. Kyle
Keyword(s):  
Open Source ◽  
Single Point ◽  
Standard Of Care ◽  
Current Standard ◽  
Content Type ◽  
Cutaneous Infections ◽  
Balamuthia Mandrillaris ◽  
Free Living Amoeba ◽  
Malaria Box

ABSTRACT Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibited the growth of B. mandrillaris in vitro. Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.

scholarly journals Fatal Granulomatous Amebic Encephalitis Due to Balamuthia mandrillaris in New Mexico: A Case Report

2014 ◽  
Vol 1 (2) ◽  
Author(s):  
Talia N. Pindyck ◽  
Lauren E. Dvorscak ◽  
Blaine L. Hart ◽  
Michael D. Palestine ◽  
Joel E. Gallant ◽  
...  
Keyword(s):  
Case Report ◽  
New Mexico ◽  
Alcohol Abuse ◽  
Free Living ◽  
Cocaine Use ◽  
Balamuthia Mandrillaris ◽  
Water Exposure ◽  
Free Living Amoeba ◽  
History Of ◽  
Amebic Encephalitis

Abstract Balamuthia mandrillaris is a free-living amoeba that can cause granulomatous amebic encephalitis (GAE). We report a case in an individual with a history of alcohol abuse, cocaine use, and ditch water exposure. This is the first reported case of GAE due to B mandrillaris in New Mexico.

Encephalitis due to a free-living amoeba (Balamuthia mandrillaris): Case report with literature review

2000 ◽  
Vol 53 (6) ◽  
pp. 611-616 ◽  
Author(s):  
Inderjit Deol ◽  
Laura Robledo ◽  
Armando Meza ◽  
Govinda S Visvesvara ◽  
Russell J Andrews
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Free Living ◽  
Balamuthia Mandrillaris ◽  
Free Living Amoeba

scholarly journals Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoebaBalamuthia mandrillaris

2018 ◽  
Author(s):  
Matthew T. Laurie ◽  
Corin V. White ◽  
Hanna Retallack ◽  
Wesley Wu ◽  
Matthew S. Moser ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Antimicrobial Agents ◽  
Survival Rates ◽  
Standard Of Care ◽  
Host Cells ◽  
Current Standard ◽  
Promising Candidate ◽  
Balamuthia Mandrillaris ◽  
Tract Infections

AbstractBalamuthia mandrillarisis a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms ofB. mandrillaris– a proliferative trophozoite form and a non-proliferative cyst form, which is highly resistant to harsh physical and chemical conditions – have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multi-drug regimens often including the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low and studies evaluating the susceptibility ofB. mandrillaristo these compounds and other potential therapeutics are limited. To address the need for more effective treatments, we screened 2,177 clinically-approved compounds forin vitroactivity againstB. mandrillaris. The quinoline antibiotic nitroxoline, which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a physiologically relevant range. We compare thein vitroefficacy of nitroxoline to drugs currently used in the standard of care for GAE and find that nitroxoline is the most potent and selective inhibitor ofB. mandrillaristested. Furthermore, we demonstrate that nitroxoline preventsB. mandrillaris-mediateddestruction of host cells in cultured fibroblast and primary brain explant models also at physiologically relevant concentrations. Together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment ofB. mandrillarisinfections.ImportanceBalamuthia mandrillarisis responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen,B. mandrillarisis understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fightB. mandrillarisinfections, mortality rates remain high even for patients receiving intensive care. This study addresses the need for new anti-amoebic drugs using a high-throughput screening approach to identify novelB. mandrillarisinhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline killsB. mandrillarisat physiologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life threateningB. mandrillarisinfections.

scholarly journals First Draft Genome Sequence ofBalamuthia mandrillaris, the Causative Agent of Amoebic Encephalitis

2015 ◽  
Vol 3 (5) ◽  
Author(s):  
H. Detering ◽  
T. Aebischer ◽  
P. W. Dabrowski ◽  
A. Radonić ◽  
A. Nitsche ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Causative Agent ◽  
Mammalian Species ◽  
Draft Genome ◽  
Draft Genome Sequence ◽  
Free Living ◽  
Balamuthia Mandrillaris ◽  
Free Living Amoeba ◽  
The Brain

The free-living amoebaBalamuthia mandrillarisis a rare but highly lethal agent of amoebic encephalitis in humans and many other mammalian species. Here, we announce the first draft genome sequence of the original 1990 isolate cultured from the brain of a deceased mandrill baboon.

scholarly journals Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the PathogenBalamuthia mandrillaris

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Matthew T. Laurie ◽  
Corin V. White ◽  
Hanna Retallack ◽  
Wesley Wu ◽  
Matthew S. Moser ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Survival Rates ◽  
Standard Of Care ◽  
Host Cells ◽  
Current Standard ◽  
Promising Candidate ◽  
Content Type ◽  
Balamuthia Mandrillaris ◽  
Tract Infections

ABSTRACTBalamuthia mandrillarisis a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms ofB. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions—have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility ofB. mandrillaristo these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds forin vitroactivity againstB. mandrillaris. The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared thein vitroefficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor ofB. mandrillaristested. Furthermore, we demonstrate that nitroxoline preventsB. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment ofB. mandrillarisinfections.IMPORTANCEBalamuthia mandrillarisis responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen,B. mandrillarisis understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fightB. mandrillarisinfections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novelB. mandrillarisinhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline killsB. mandrillarisat pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threateningB. mandrillarisinfections.

scholarly journals Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae

2020 ◽  
Author(s):  
Christopher A. Rice ◽  
Beatrice L. Colon ◽  
Emily Chen ◽  
Mitchell V. Hull ◽  
Dennis E. Kyle
Keyword(s):  
Drug Design ◽  
The United States ◽  
Neglected Diseases ◽  
High Morbidity ◽  
Naegleria Fowleri ◽  
Free Living ◽  
Structure Based Drug Design ◽  
Balamuthia Mandrillaris ◽  
Nægleria Fowleri

AbstractDiseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. In pursuit of repurposing drugs for chemotherapies, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 μM) against N. fowleri (n=19), A. castellanii (n=12), and B. mandrillaris (n=27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.Author SummaryFree-living amoebae (FLA) are ubiquitous in soil and freshwater and most are non-pathogenic to people; however, three different pathogenic FLA have been found to cause severe, most often fatal diseases in humans. Due to poor detection and inadequate treatment options available for pathogenic FLA, the fatality rates are still > 90% for the diseases caused by Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba spp. With hundreds of cases in the United States and many more cases reported worldwide, there is still an urgent clinical need for effective diagnosis and specific treatments discovered against these opportunistic parasites. Drug repurposing is a powerful approach for drug-discovery because it significantly improves the discovery time, reduces the amount of resources, and decreases costs required to advance lead candidate drugs of interest into the clinic. This is extremely helpful for neglected diseases including pathogenic FLA where there is a need for new active therapies with limited budgets. This report addresses the discovery of new active drugs with potential for repurposing, multiple new drug classes that inhibit pathogenic FLA, and numerous putative drug targets that can be used as tools for further investigation and structure-based drug design.

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